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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 381, Issue 2, pp 147–152 | Cite as

Ivermectin is a nonselective inhibitor of mammalian P-type ATPases

  • Paulo Henrique Cotrim Pimenta
  • Claudia Lucia Martins Silva
  • François NoëlEmail author
ORIGINAL ARTICLE

Abstract

Ivermectin is a large spectrum antiparasitic drug that is very safe at the doses actually used. However, as it is being studied for new applications that would require higher doses, we should pay attention to its effects at high concentrations. As micromolar concentrations of ivermectin have been reported to inhibit the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), we decided to investigate its putative inhibitory effect on other two important P-type ATPases, namely the Na+ , K+-ATPase and H+/K+-ATPase. We first extended the data on SERCA, using preparations from rat enriched in SERCA1a (extensor digitorum longus) and 1b (heart) isoforms. Secondly, we tested the effect of ivermectin in two preparations of rat Na+, K+-ATPase in order to appreciate its putative selectivity towards the α1 isoform (kidney) and the α23 isoforms (brain), and in an H+/K+-ATPase preparation from rat stomach. Ivermectin inhibited all these ATPases with similar IC50 values (6–17 µM). With respect to the inhibition of the Na+, K+-ATPase, ivermectin acts by a mechanism different from the classical cardiac glycosides, based on selectivity towards the isoforms, sensibility to the antagonistic effect of K+ and to ionic conditions favoring different conformations of the enzyme. We conclude that ivermectin is a nonselective inhibitor of three important mammalian P-type ATPases, which is indicative of putative important adverse effects if this drug were used at high doses. As a consequence, we propose that novel analogs of ivermectin should be developed and tested both for their parasitic activity and in vitro effects on P-type ATPases.

Keywords

Ivermectin ATPase SERCA ATPase, Na-K H/K-ATPase Adverse effect 

Abbreviations

DMSO

dimethyl sulfoxide

EDTA

ethylenediaminetetraacetic acid

HEPES

4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

PMSF

phenylmethylsulfonyl fluoride

POPOP

1,4-bis-[2-(5-phenyloxazolyl)]-benzene

PPO

2,5-diphenyloxazole

Tris

tris(hydroxymethyl)aminomethane

Notes

Acknowledgments

Financial support was provided by Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. F. Noël and PHC Pimenta were fellows of CNPq.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Paulo Henrique Cotrim Pimenta
    • 1
  • Claudia Lucia Martins Silva
    • 1
  • François Noël
    • 1
    Email author
  1. 1.Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Bloco J do Centro de Ciências da Saúde, sala 17Universidade Federal do Rio de Janeiro, Cidade UniversitáriaIlha do FundãoBrazil

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